Autosomal Recessive Congenital Dyserythropoietic Anemia Type III Is Caused By Mutations in the Centralspindlin RACGAP1 Component

Abstract

An autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III) is caused by a missense mutation in the KIF23 gene whose protein product, mitotic kinesin-like protein (MKLP1), is part of the centralspindlin complex involved in cytokinesis. Several case reports suggested the existence of an autosomal recessive inheritance form of CDA III so far not genetically characterized. By means of whole exome sequencing in a Spanish CDA III family with healthy parents, we identified in the male proband a novel homozygous missense mutation p.Pro432Ser in the RACGAP1 gene, which encodes for the RACGAP1 protein (Rac GTPase-activating protein 1, also known as MgcRacGAP or CYK-4), the partner of MKLP1 in the centralspindlin complex. A second CDA III Spanish patient has a different rare and novel homozygous missense mutation, p.Thr220Ala, in the RACGAP1 gene. Both patients presented with macrocytic anemia, aberrant multinucleated erythroblasts in the bone marrow typically seen in CDA III cases, no iron overload and skull defects secondary to severe anemia. Silencing of RACGAP1 using siRNA in HeLa cells mimics the cytokinesis defect observed in the bone marrow of our patients. Both mutations disrupt normal cytokinesis and alter the GTPase balance in patients' cells. We conclude that the autosomal recessive form of CDA type III is caused by mutations in the RACGAP1 gene, encoding for RACGAP1 protein, which is the partner of MKLP1 in the centralspindlin complex critical for cytokinesis and now both proteins are associated with CDA type III. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling

“…Thus, CHD8 appears to maintain a balance of Rho GTPase signaling genes essential for erythroblast cytokinesis. Interestingly, such a mechanism of erythroblast regulation mimics that reported recently for CDA III patients ( Romero-Cortadellas et al, 2021 ; Wontakal et al, 2022 ).…”

“…In humans, bi- and multi-nucleated erythroblasts are associated with CDA caused by mutations in several genes, including CDAN1 , CDIN1 , SEC23B , KIF23 , GATA1 , and KLF1 ( Iolascon et al, 2020 ). Two recent studies identified RACGAP1 mutations resulting in unbalanced Rho GTPase activities and CDA III subtype ( Romero-Cortadellas et al, 2021 ; Wontakal et al, 2022 ). Our findings suggest that loss of CHD8 leads to a CDA-like phenotype associated with dysregulation of Rho signaling.…”

“…Cdc42 also plays an important role in cytokinesis, nuclear polarization, and nuclear extrusion during erythroblast differentiation ( Ubukawa et al, 2020 ). Recent studies have found that a precise balance of the activities of Rho GTPases, maintained by RACGAP1 , is required for erythroblast cytokinesis, the disruption of which can be causal for a subtype of congenital dyserythropoietic anemia, CDA III ( Romero-Cortadellas et al, 2021 ; Wontakal et al, 2022 ).…”

The congenital dyserythropoieitic anemias: genetics and pathophysiology

“…Recently, mutations in RACGAP1, which encodes the Rac GTPase-activating protein 1 (MgcRac-GAP, also known as CYK-4), have been described in families with an autosomal recessive form of CDA III [96 ▪▪ ,97], raising the possibility that defects in KIF23 and RACGAP1 may result in CDA III via a common mechanism, as both proteins are components of centralspindlin [98]. However, this remains speculative and requires further investigation.…”